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Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

Christopher Duncan 1, * Benjamin Thompson 1 Rui Chen 1 Gillian Rice 2 Florian Gothe 1, 3 Dan Young 4 Simon Lovell 2 Victoria Shuttleworth 1 Vicky Brocklebank 1 Bronte Corner 1 Andrew Skelton 1 Vincent Bondet 5 Jonathan Coxhead 1 Darragh Duffy 5 Cécile Fourrage 6 John Livingston 7 Julija Pavaine 8, 2 Edmund Cheesman 8 Stephania Bitetti 8 Angela Grainger 1 Meghan Acres 1 Barbara Innes 1 Aneta Mikulasova 1 Ruyue Sun 1 Rafiqul Hussain 5 Ronnie Wright 2, 8 Robert Wynn 9 Mohammed Zarhrate 10 Leo Zeef 2 Katrina Wood 11 Stephen Hughes 9, 8 Claire Harris 1 Karin Engelhardt 1 Yanick Crow 10, 12, 13 Richard Randall 4 David Kavanagh 1, 11 Sophie Hambleton 1, 11, * Tracy Briggs 2, 8, *
* Corresponding author
1 Newcastle University [Newcastle]
2 University of Manchester [Manchester]
3 LMU - Ludwig-Maximilians-Universität München
4 University of St Andrews [Scotland]
5 Immunobiologie des Cellules dendritiques
6 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
7 University of Leeds
8 Central Manchester University Hospitals NHS Foundation Trust
9 Royal Manchester Children's Hospital
10 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
11 Newcastle Upon Tyne Hospitals NHS Foundation Trust
12 UPD5 - Université Paris Descartes - Paris 5
13 University of Edinburgh
Abstract : Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
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Submitted on : Tuesday, January 7, 2020 - 10:36:53 AM
Last modification on : Wednesday, November 24, 2021 - 9:54:14 AM

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Christopher Duncan, Benjamin Thompson, Rui Chen, Gillian Rice, Florian Gothe, et al.. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2. Science Immunology, American Association for the Advancement of Science, 2019, 4 (42), pp.eaav7501. ⟨10.1126/sciimmunol.aav7501⟩. ⟨pasteur-02430168⟩

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